Hypercholesterolemia exacerbates in-stent restenosis in rabbits: Studies of the mitigating effect of stent surface modification with a CD47-derived peptide

• Published in: Atherosclerosis Vol. 390; p. 117432
• Main Authors: Fishbein, Ilia, Inamdar, Vaishali V., Alferiev, Ivan S., Bratinov, George, Zviman, Menekhem M., Yekhilevsky, Anna, Nagaswami, Chandrasekaran, Gardiner, Kristin L., Levy, Robert J., Stachelek, Stanley J.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2024
• Subjects: CD47; Hypercholesterolemia; In-stent restenosis; Inflammation; Rabbit model; Stent surface modification; Stents; Stent surface modification; Hypercholesterolemia; Rabbit model; In-stent restenosis; Inflammation; CD47; Stents
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2023.117432

Hypercholesterolemia (HC) has previously been shown to augment the restenotic response in animal models and humans. However, the mechanistic aspects of in-stent restenosis (ISR) on a hypercholesterolemic background, including potential augmentation of systemic and local inflammation precipitated by HC, are not completely understood. CD47 is a transmembrane protein known to abort crucial inflammatory pathways. Our studies have examined the interrelation between HC, inflammation, and ISR and investigated the therapeutic potential of stents coated with a CD47-derived peptide (pepCD47) in the hypercholesterolemic rabbit model. PepCD47 was immobilized on metal foils and stents using polybisphosphonate coordination chemistry and pyridyldithio/thiol conjugation. Cytokine expression in buffy coat-derived cells cultured over bare metal (BM) and pepCD47-derivatized foils demonstrated an M2/M1 macrophage shift with pepCD47 coating. HC and normocholesterolemic (NC) rabbit cohorts underwent bilateral implantation of BM and pepCD47 stents (HC) or BM stents only (NC) in the iliac location. A 40 % inhibition of cell attachment to pepCD47-modified compared to BM surfaces was observed. HC increased neointimal growth at 4 weeks post BM stenting. These untoward outcomes were mitigated in hypercholesterolemic rabbits treated with pepCD47-derivatized stents. Compared to NC animals, inflammatory cytokine immunopositivity and macrophage infiltration of peri-strut areas increased in HC animals and were attenuated in HC rabbits treated with pepCD47 stents. Augmented inflammatory responses underlie severe ISR morphology in hypercholesterolemic rabbits. Blockage of initial platelet and leukocyte attachment to stent struts through CD47 functionalization of stents mitigates the pro-restenotic effects of hypercholesterolemia. [Display omitted] •CD47-derived peptide (pepCD47) immobilized on a metal substrate decreases cell attachment to the surface.•Immobilized pepCD47 promotes M2 polarization of macrophages.•Hypercholesterolemia increases the severity of ISR in rabbits.•PepCD47 stents reduce in-stent restenosis (ISR) severity in hypercholesterolemic rabbits.•PepCD47-mediated reduction of arterial inflammation mitigates ISR.